COVID-19 in the Initiation and Progression of Atherosclerosis

The incidence of atherosclerotic cardiovascular disease is increasing globally, especially in low- and middle-income countries, despite significant efforts to reduce traditional risk factors. Premature subclinical atherosclerosis has been documented in association with several viral infections. The magnitude of the recent COVID-19 pandemic has highlighted the need to understand the association between SARS-CoV-2 and atherosclerosis. This review examines various pathophysiological mechanisms, including endothelial dysfunction, platelet activation, and inflammatory and immune hyperactivation triggered by SARS-CoV-2 infection, with specific attention on their roles in initiating and promoting the progression of atherosclerotic lesions. Additionally, it addresses the various pathogenic mechanisms by which COVID-19 in the post-acute phase may contribute to the development of vascular disease. Understanding the overlap of these syndromes may enable novel therapeutic strategies. We further explore the need for guidelines for closer follow-up for the often-overlooked evidence of atherosclerotic cardiovascular disease among patients with recent COVID-19, particularly those with cardiometabolic risk factors.

pathogen effects, the resultant systemic or organ-specific inflammatory response may drive atherosclerosis initiation and progression. 6Furthermore, inflammation can trigger a local vascular reaction within arterial plaques, resulting in plaque disruption, thrombosis, and acute ischemic events. 6nsidering the global impact of the COVID-19 pandemic, 7 it is imperative to understand its association with atherosclerosis.
Endothelial cell (EC) dysfunction, an early event, and the subsequent platelet activation and adhesion to the activated endothelium are central to both atherosclerosis 3 and COVID-19, 8,9 suggesting a major link between them.Though other viral infections 10 can trigger pro-inflammatory cytokine release, the immune overactivation in SARS-CoV-2 infection is particularly severe, enhancing EC dysfunction and perpetuating this vicious cycle. 8r review focuses on the various pathophysiological mechanisms triggered by SARS-CoV-2 infection that can initiate and promote atherosclerotic lesions.Given the high frequency of persistent symptoms and sequelae in patients who recovered from COVID-19, 11 we also explore the pathogenesis of vascular disease in long-COVID-19 and the need for guidelines for follow-up and evaluation of ASCVD, particularly among those with cardiometabolic risk factors.

CLINICAL CORONARY SYNDROMES DURING THE ACUTE PHASE
Patients with pre-existing cardiovascular disease and risk factors have a worse prognosis with COVID-19. 12,13Conversely, the acute phase of COVID-19 is linked to acute ischemic events. 14ound 20% of hospitalized patients with COVID-19 exhibit myocardial injury, as evidenced by elevated cardiac troponins, 15 likely secondary to plaque rupture, coronary spasm, microthrombi, myocarditis, cytokine storm, or direct endothelial or vascular injury.Although individual autopsy studies reveal varying observations regarding lymphocytic myocarditis in COVID-19-associated myocardial injury, 16,17 a systematic review of cardiac findings from postmortem studies identified myocardial cell necrosis and myocardial edema as the most common findings, with instances of focal or multifocal myocarditis being relatively minor. 18The systematic review also notes a median prevalence of 36.2% for microthrombi and 11.8% for acute MI. 18 In 2 case series, nearly 30 to 40% COVID-19 patients with ST-segment elevation myocardial infarction (STEMI) showed nonobstructed coronaries on invasive angiography. 14,19A North American registry with 1,185 patients 20 highlighted the absence of a culprit artery in almost 20% of patients undergoing angiography for STEMI with confirmed or suspected COVID-19. 20The findings suggest viral effects beyond plaque destabilization, highlighting direct and indirect pathways to cardiac injury.

HIGHLIGHTS
SARS-CoV-2 infection can markedly influence the initiation and progression of atherosclerotic lesions.
Endothelial dysfunction, platelet activation, and persistent inflammation are potential drivers of increased atherosclerosis following COVID-19.
Understanding the pathogenesis of atherosclerosis in COVID-19 can provide insights into cardiovascular disease mechanisms in other chronic infections.
Recognizing the cardiovascular implications of long COVID-19 highlights the importance of proactive risk management and advocates for further research into this topic.

COVID-19 and Atherosclerosis
A U G U S T 2 0 2 4 : 1 0 1 1 0 7 STEMI patients with concurrent COVID-19 faced higher risks, including in-hospital death, stroke, recurrent MI, or repeat unplanned revascularization compared to matched pre-COVID-19 STEMI patients. 20A UK retrospective cohort of patients with STEMI reported that those with concurrent COVID-19 had higher troponin levels, modified thrombus grades, and rates of multivessel thrombosis, as well as increased use of glycoprotein IIb/IIIa inhibitors than those without COVID-19. 21Atherosclerotic plaque rupture and arterial thrombus formation in these patients are likely due to EC dysfunction, platelet activation, and concomitant systemic inflammation. 22ese very similar mechanisms are also key to the initiation and progression of atherosclerosis and are further explored below.

ENDOTHELIAL DYSFUNCTION ROLE IN ATHEROSCLEROSIS.
The endothelium has important functions in inflammation, immune modulation, vascular tone maintenance, and hemostasis. 23EC dysfunction, an early step in atherosclerosis preceding clinical symptoms, can be triggered by oxidized cholesterol, hyperglycemia, infection, inflammation, and hemodynamic processes. 24tably, pathogen-and damage-associated molecular patterns (PAMPs and DAMPs, respectively), pro- or EC injury (apoptosis and necrosis) 24 (Figure 1).In type I EC activation (self-limited), immediate release of prestored proteins occurs, 25

SIGNALING PATHWAYS AND OTHER MECHANISMS
The transcription factor NF-kB, crucial

COVID-19 and Atherosclerosis
in EC activation toward a pro-inflammatory phenotype, is primed for greater activation in atherosclerosis-prone arterial regions. 46Several pathogenic stimuli for EC dysfunction stimulate pattern recognition receptors (PRRs) like Toll-like receptors (TLRs) 46  inflammation and atherosclerosis. 57,58Monocytes and lymphocytes bind to VCAM-1 on ECs via the counterreceptor VLA-4 (integrin a4b1) and to ICAM-1 via LFA-1(integrin aLb2). 57,58Plasma levels of soluble sVCAM-1 and sICAM-1 correlate with atherosclerotic lesion burden 59 and predict future cardiovascular events. 59 COVID-19, elevated plasma levels of sVCAM-1 and sICAM-1 correlate with disease severity. 60While the precise mechanism of elevation of ICAM-1 and VCAM-1 in SARS-CoV-2 infection is unclear, it appears to be driven by virus-induced inflammatory response and EC activation. 61Severe COVID-19 triggers a cytokine storm, leading to upregulation of these adhesion molecules, facilitating leukocyte adhesion and migration, exacerbating vascular inflammation.
Rotoli et al 62 68 Chidambaram et al activating ECs and innate immune cells. 71ATELETS AND COVID-19.Though the majority of platelets becomes hyperactivated in COVID-19, 9,72,73 a small fraction becomes functionally defective. 74The mechanisms of interaction between SARS-CoV-2 and platelets and/or megakaryocytes remain a subject of debate.

COVID-19 and Atherosclerosis
D i r e c t i n t e r a c t i o n a n d i n t e r n a l i z a t i o n o f S A R S -C o V -2 i n t o p l a t e l e t s .Direct interaction of SARS-CoV-2 with platelets and hyperactivation was proposed following SARS-CoV-2 RNA detection in platelets of COVID-19 patients. 9,72Although an ACE2dependent 75 interaction was hypothesized, platelet
Activated platelets express markers like P-selectin, CD40L, TLRs, FcgRIIA, and activated integrin GP IIb IIIa, enhancing aggregation, degranulation (serotonin and PF4), and the release of extracellular vesicles. 7240 L on activated platelets triggers EC activation and secretion of MCP-1 and IL-8. 83MCP-1 production, additionally attributed to endothelial NF-kB activation by platelet-derived IL-1b 84 and platelet adhesion to SMCs, augments SMC migration, which is crucial for atherogenesis.
Interactions between platelet P-selectin and leukocyte P-selectin glycoprotein ligand-1 facilitate leukocyte transmigration 85 and influence plaque initiation and their cellularity.Interaction with Pselectin glycoprotein ligand-1 stimulates P-selectin shedding, 85 with elevated soluble P-selectin (sPselectin) levels in plasma being linked to an increased risk of MI and stroke. 86gardless of COVID-19 severity, platelets exhibit increased expression of P-selectin and CD40 L, 9 enhancing platelet-leukocyte interactions and TF expression. 9,72,73Treatment with crizanlizumab, tar- pathways.Normally, NF-kB is inactive, bound to IkB in the cytosol.In the canonical pathway, inflammatory stimuli activate the IkB Kinase (IKK) complex (IKKa, b, g or NEMO), leading to IkB phosphorylation, ubiquitination, and degradation.This releases NF-kB to enter the nucleus and initiate transcription of target genes including CAMs, pro-inflammatory factors, including TNF-a, IL-6, and IL-   (Figure 4).
TLR3 activation enables TRIF signaling, leading to IFN production. 97Studies highlight the role of TLR2 in innate immune activation in COVID-19, 98 alongside TLR1, TLR4, and TLR6, with TLR4 demonstrating the highest affinity for the virus. 99Additionally, TLR7 and TLR8 are known to recognize antiphospholipid antibodies 100 found in patients with severe COVID-19.Cytokine signaling and cell death.Severe COVID-19 triggers a systemic inflammatory response, leading to multi-organ damage. 13Elevated cytokines (IL-1b, IL-6, TNF-a, IFN-g, macrophage inflammatory protein 1a and 1b) and chemokines (CCL-2, CCL-3, and CCL-5) correlate with higher viral loads 106 and worse COVID-19 prognosis. 13,106ECs, when exposed to pro-inflammatory cytokines, initiate transcriptional programs, inducing the expression of adhesion molecules and chemokines, promoting leukocyte recruitment and inflammation. 107This results in EC injury, increased vascular permeability, and end-

COVID-19 and Atherosclerosis
A U G U S T 2 0 2 4 : 1 0 1 1 0 7 organ damage. 108Through this amplification loop, ECs constitute a significant source of proinflammatory cytokines, characteristic of the cytokine storm in COVID-19. 108This excessive inflammation can persist due to pre-existing cardiometabolic risk factors and promote atherogenesis independent of hyperlipidemia. 109o t e n t i a l t h e r a p i e s t a r g e t i n g k e y i n t e r m e d i a t e s i n i n fl a m m a t i o n .Canakinumab, an IL-1b neutralizing antibody, reduced major adverse cardiovascular events in the CANTOS trial, 110 while anakinra, inhibiting both IL-1a and IL-1b, was shown to reduce inflammatory markers post-NSTEMI. 111Both agents improved the duration of hospital stay and shortterm outcomes in patients with moderate-to-severe COVID-19. 112,113The utility of IL-1 inhibitors in COVID-19-related atherosclerosis warrants further investigation.
IL-6 inhibitors, like tocilizumab and ziltivekimab, have demonstrated cardiovascular benefits, including attenuated inflammatory response and decreased troponin release post-PCI in NSTEMI patients. 114They also showed improved myocardial salvage, as measured by magnetic resonance imaging, in patients with STEMI. 115Additionally, in severe COVID-19 patients, tocilizumab reduced short-term mortality as demonstrated in the REMAP-CAP 116 and RECOVERY trials, 117 underscoring its potential in acute inflammatory settings and possibly in COVID-19-related cardiovascular complications.
Colchicine, while not directly beneficial in the prognosis of COVID-19, has shown significant antiinflammatory properties in cardiovascular settings.
It downregulates E-selectin expression and decreases NLPR3 inflammasome activation, suppressing IL-1b and IL-6 release, which are critical inflammatory mechanisms in atherosclerosis. 118A meta-analysis revealed that low-dose colchicine reduced the risk of major adverse cardiovascular and the need for coronary revascularization across a broad spectrum of patients with coronary disease. 119Currently, no studies have evaluated targets in the inflammatory pathways regarding post-COVID-19 atherosclerosis.A comprehensive discussion of potential therapies is beyond the scope of this manuscript; readers are referred to more detailed reviews elsewhere. 120,121

POST-ACUTE SEQUELAE OF COVID-19
Post-acute sequelae of COVID-19 (PASC), also called post-acute COVID-19 syndrome or long-COVID, involves sequelae 1 to 3 months after SARS-CoV-2 infection, 122,123 with major cardiac symptoms including fatigue, dyspnea, chest pain, and palpitations. 124,125While several reports highlight myocarditis, postural orthostatic tachycardia syndrome, arrhythmias, and venous thromboembolism, 123,126 there is growing attention to the long-term risk of subclinical vascular pathology and clinical coronary artery disease, as nearly one-third of PASC patients and half of cardiac referrals post-COVID-19 report chest pain. 124,125Although the true ASCVD burden post-acute COVID-19 remains undefined, emerging studies suggest an increased risk (Table 1).
The influence of various SARS-CoV-2 variants, COVID-19 vaccination, 139 and in-hospital therapies 140 on the risk of developing ASCVD post-COVID-19 remains an area for future investigation.The pathogenic mechanisms implicated in long COVID-19related ASCVD are detailed below and depicted in the Central Illustration.
PATHOGENIC MECHANISMS IN PASC.V i r a l a n t i g e n p e r s i s t e n c e .Besides infectious particles in airways during acute COVID-19, viral RNA and antigens are detected in the central nervous system and lymphoid organs, 141 as well as in the feces for months. 142However, these RNA or antigen reservoirs 143 in PASC do not appear to reflect persistent or latent viral infection, as the virus cannot be cultured from these sources. 142 sponses, 145 often increasing over time, 145,146 which are independent of COVID-19 vaccination status 147 and unrelated to prolonged viral replication or denovo antigen production. 148 In acute COVID-19, T cells and NK cells decline due to SARS-CoV-2-induced apoptosis. 153However, 9 to 12 months postinfection, PASC patients exhibited increased CD4þ and CD8þ effector T cells, Th9 cells, and naive B cells, 154 arguing against sustained T-cell dysfunction. 147After infection, heightened Th9 154

COVID-19 and Atherosclerosis
and Th17 CD4þ subsets emerged, 155 opposing the induction of Treg cells, which protect against atherogenesis.Convalescent subjects displayed CD69þ CD103-CD8þ T cells expressing EOMES, granzyme B, and granzyme K, which are linked to fibroblast activation and advanced atherosclerosis. 156u t o i m m u n i t y .Severe COVID-19 and PASC may accompany persistent, general, or tissue-specific 157 (blood vessels, heart, or brain) autoimmune responses, likely secondary to transient loss of self-tolerance or inappropriate immune reconstitution. 154itially thought to sustain viral reservoirs, anti-IFN type I antibodies do not contribute to PASC. 158Autoantibodies associated with atherosclerosis, like antinuclear antibodies, ACA (anti-cardiolipin antibody), and b2GP1 autoantibodies, were observed in PASC patients, 159,160 suggesting possible autoimmunity following acute COVID-19.However, there is no conclusive evidence regarding the significance of SARS-CoV-2-directed antibodies in relation to long

CONCLUSIONS
With increasing awareness and accumulating evidence regarding cardiovascular involvement during infarction NF-kB = nuclear factor kappalight-chain-enhancer of activated B cells NO = nitric oxide PF4 = platelet factor 4 PRR = pattern recognition receptor ROS = reactive oxygen species SMC = smooth muscle cell STEMI = ST-segment elevation myocardial infarction TF = tissue factor TLR = Toll-like receptor TNF = tumor necrosis factor VCAM = vascular cell adhesion molecule Chidambaram et al J A C C : A D V A N C E S , V O L . 3 , N O .8 , 2 0 2 4

FIGURE 2
FIGURE 2 Role of ACE2 and Oxidative Stress in COVID-19 Furthermore, it is essential to note that future studies are needed to determine whether modulation of ACE2-SARS-CoV-2 interaction or the renin-angiotensin system could mitigate ASCVD following COVID-19.A C E 2 -i n d e p e n d e n t c e l l s u r f a c e r e c e p t o r s .Several ACE2-independent cell surface receptors have been proposed for SARS-CoV-2.Neuropilins, highly expressed in ECs and epithelial cells, influence vascular permeability and immune regulation.43Neuropilin 1, a coreceptor of vascular endothelial growth factor in ECs, is implicated in SARS-CoV-2 infectivity via interactions with unique Furingenerated substrates of S1.43 CD147, another EC receptor, facilitates dose-dependent SARS-CoV-2 entry in ACE2-deficient cells.44While these EC surface receptors may represent alternate viral entry pathways, further in-vivo validation is needed.As detailed below, current evidence points more toward indirect mechanisms, including immune cell and platelet activation, as well as increased circulating pro-inflammatory cytokines, for the EC dysfunction observed in severe COVID-19 and depend on subsequent NF-kB signaling.This induces the expression of proinflammatory cytokines (IL-1, IL-6, IL-8, IL-12, and TNF-a), adhesion molecules, and chemokines (MCP-1, IL-18, and RANTES), driving atherosclerosis via EC dysfunction, leukocyte infiltration, and SMC migration and proliferation.47While mechanisms of NF-kB activation, such as increased oxidative stress seen in other viral infections, including influenza,48 HIV,49 and HTLV-1,50 are also present in COVID-19, 51 pathways unique to SARS-CoV-2 infection exist.The SARS-CoV-2 S protein promotes NF-kB nuclear translocation through IkBa degradation, increasing expression of adhesion molecules, FVIII, TF, and pro-inflammatory cytokines (TNF-a, IL-1b, and IL-6).52Furthermore, the SARS-CoV-2 nucleocapsid (N) protein enhances the association between the TAK1 (transforming growth factor-b activated kinase 1) and IKK (IkB kinase) complex, facilitating NF-kB hyperactivation.53On the other hand, ACE2-deficient ECs, resistant to SARS-CoV-2 infection, showed increased activation compared to those expressing ACE2, possibly due to NF-kB upregulation following TLR4 activation; conversely, a TLR4 antagonist inhibited this activation.54Furthermore, the SARS-CoV-2 S and N proteins activate ECs through TLR-2/NF-kB and mitogenactivated protein kinase pathways, inducing inflammation without viral entry.55Such NF-kB upregulation in COVID-19, through the aforementioned pathways, subsequently potentiates the inflammatory response.52Furthermore, NF-kB modulates the NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domaincontaining-3) inflammasome, enhancing immune activation in COVID-19. 56Although NF-kB activation may play a role in the pathogenesis of COVID-19related atherosclerosis, future studies are needed to evaluate whether drugs modulating NF-kB are beneficial in this aspect.Increased expression of VCAM-1 and ICAM-1.The expression of VCAM-1 and ICAM-1, which are localized to the endothelium in atherosclerosissusceptible arterial regions, precedes monocyte recruitment and forms important links between IN ATHEROSCLEROSIS.Platelets and platelet-derived factors play wellcharacterized roles in atherosclerosis initiation and progression 70 : 1) platelet adhesion to endothelium and formation of platelet-leukocyte heterotypic aggregates, enabling leukocyte transmigration; and 2) release of pro-inflammatory cytokines and chemokines, such as platelet factor 4 (PF4), by activated platelets and platelet-monocyte aggregates,

FIGURE 4
FIGURE 4 Inflammatory and Immune Mechanisms in the Association of COVID-19 and Atherosclerosis demonstrated the ability of platelets to internalize SARS-CoV-2 without supporting replication, leading to viral degradation.These platelets fail to activate and undergo morphological changes, like membrane budding and ultimately programmed cell death, 79 partly explaining the thrombocytopenia in COVID-19 patients.Released extracellular vesicles from these platelets further amplify immune and cytokine dysregulation. 74I n d i r e c t i n t e r a c t i o n s w i t h p l a t e l e t s .Despite divergent mechanisms proposed for SARS-CoV-2 platelet interactions, consensus exists that platelet activation occurs during COVID-19.Puhm et al observed no platelet activation even at high viral concentrations without coagulation factors, suggesting that direct platelet-SARS-CoV-2 interactions might be too rare to explain platelet hyperactivation. 80Instead, in COVID-19 patients, elevated TF levels, arising from activated ECs and macrophages, 81 initiate the coagulation cascade with subsequent thrombin generation, which, even under low concentrations, may potentially activate platelets via protease-activated receptor-1 and -4. 82P l a t e l e t a d h e s i o n a n d a c t i v a t i o n , C D 4 0 L , a n d P -s e l e c t i n .EC dysfunction leads to NO-prostacyclin imbalance, as well as upregulation of endothelial

FIGURE 4
FIGURE 4 Continued Pro-inflammatory cytokines, IL-1b and TNF-a, Induce monocyte transmigration, differentiation into macrophages, and foam cell formation in atherosclerotic plaques.The Th1 response exacerbates atherosclerosis; IL-12 and IL-18 from macrophages promote Th1 Differentiation and IFN-g secretion, which disrupts endothelial junctions, enhances monocyte infiltration, foam-cell formation, smooth muscle proliferation, and plaque destabilization.Image inset: activation of PRRs in SARS-CoV-2.SARS-CoV-2 spike protein binds to ACE2, is internalized into endosomes post-cathepsin-mediated cleavage, releasing viral RNA.Innate immune cells detect this through PRRs like TLRs, RLRs, and NLRs.Many viruses activate TLR signal transduction via MyD88, except TLR3, which uses TRIF, activating NF-kB, MAPKs, and IRF transcriptional profiles of megakaryocytes, with subsequent transfer of mRNA transcripts to newly formed platelets.9Hence, platelets and ECs mutually amplify the inflammatory response in COVID-19.Though the role of platelet hyperactivation in thrombosis and coagulopathy in COVID-19 is well established, further research into the abovedescribed putative pathways linking platelet dysfunction in COVID-19 to atherosclerosis is essential to elucidate the precise mechanisms.Additional studies are necessary to determine whether drugs targeting these pathways offer therapeutic benefits in this aspect.ROLE OF INFLAMMATION AND IMMUNITYIMMUNE RESPONSE AND ATHEROSCLEROSIS.Inflammatory processes, along with the innate and adaptive immune system, drive the initiation and progression of atherosclerosis3 and are associated with future cardiovascular events beyond traditional cardiovascular risk factors.Inflammation triggers EC dysfunction, platelet activation, monocyte transmigration, and foam cell formation.90The peripheries of atherosclerotic plaques contain abundant innate (activated macrophages, dendritic cells, and NK-T-Cells) and adaptive (T cells) immune cells.TNF-a and IL-1 are especially relevant, as they promote the expression of other cytokines, CAMs, and vascular SMC migration and mitogenesis.3Although T cells generally exacerbate atherosclerosis (specifically the pro-atherogenic Th1 response), certain subsets limit inflammation and plaque complications.Antigen exposure and IL-12 and IL-18 from macrophages induce Th1 differentiation91,92 and IFN-g secretion, promoting atherosclerosis via EC junction disruption, foam-cell formation, matrix degradation, and plaque destabilization.93The role of CD8þ T cells in atherosclerosis remains unclear, while Treg cells have well-known anti-atherosclerotic properties.94INNATE IMMUNITY AND COVID-19.The innate immune system is crucial in every step of SARS-CoV-2's interaction with host cells, influencing viral entry, association with PRRs, initiation of signaling pathways, and cytokine production.

Figure 4
illustrates the inflammatory and immune mechanisms linking COVID-19 and atherosclerosis.S A R S -C o V -2 v i r a l e n t r y a n d P R R s e n s i n g .Upon SARS-CoV-2 S protein binding to the ACE2 receptor, the virus either releases its genomic RNA into the cytoplasm after viral-host membrane fusion28 or is internalized into endosomes after cathepsin-mediated cleavage.95Key innate immune cells possess PRRs in the cell surface, endosomes, or cytoplasm to respond to PAMPs or DAMPs.96PRRs relevant in COVID-19 include TLRs, RIG I-like receptors, and NOD-like receptors.Viruses often trigger TLR signaling via MyD88; however, TLR3 signals exclusively through TRIF, activating downstream NF-kB, mitogen-activated protein kinases, and IFN regulatory factors.Their nuclear translocation results in the transcriptional activation of pro-inflammatory cytokines (eg, TNF-a, IL-6, and IL-1) and innate immune sensors like NLRP3

Furthermore
, RIG I-like receptors (MDA-5 and RIG-1), which are key IFN pathway regulators, sense the intracellular single-stranded RNA of SARS-CoV-2. 101I n fl a m m a s o m e a c t i v a t i o n .Inflammasomes, particularly NLRP3, are ring-like structures that assemble upon innate immune activation (Figure 4) and are pivotal in atherosclerosis by converting pro-IL-1b to IL-1b and enhancing expression of endothelial adhesion molecules (E-selectin, ICAM-1, and VCAM-1). 102Additionally, neutrophil extracellular traps, cholesterol crystals, ox-LDL cholesterol, and shear stress contribute to NLRP3 inflammasome assembly in atherosclerosis. 103SARS-CoV-2 activates NLRP3 inflammasome directly or indirectly, triggering cytokine (IL-1b and IL-18) release and activation of the pyroptosis pathway. 104Colchicine, an NLRP3 inflammasome inhibitor, has been found to improve outcomes in COVID-19 patients. 105Thus, NLRP3 inflammasome may amplify the inflammation associated with COVID-19, potentially accelerating the progression of atherosclerosis.
Peluso et al demonstrated circulating SARS-CoV-2 S protein in PASC patients 12 months post-diagnosis, but N protein less frequently, arguing against active viral reservoirs. 144I m m u n e m e c h a n i s m s a n d d y s r e g u l a t i o n .Postinfection, most patients generate long-lasting SARS-CoV-2-specific CD4 þ and CD8 þ T-cell and B-cell re- At 6 months, S-specific CD4þ TCR clonal depth correlated with COVID-19 severity and long COVID symptoms, 149 while CD8 þ T-cell responses correlated with pre-existing lung disease.Follicular dendritic cells retain SARS-CoV-2 antigens in germinal centers for months, driving memory B-cell maturation, 146 with unique immunoglobulin signatures in PASC patients. 150Vaccinated individuals showed reduced risk 151 and earlier resolution of long COVID-19 symptoms, 152 possibly due to faster return to immunological baseline or antigen clearance.

CENTRAL 4 COVID
ILLUSTRATION Various Factors and Mechanisms Triggering the Initiation of Atherosclerosis During the Acute and Post-Acute Phases of COVID-19 Chidambaram V, et al.JACC Adv.2024;3(8):101107.High-risk groups need to be identified for screening and long-term follow-up after COVID-19.CMR ¼ cardiac magnetic resonance; CTA ¼ computed tomographic angiography; ECG ¼ electrocardiogram.Chidambaram et al J A C C : A D V A N C E S , V O L . 3 , N O .8 , 2 2

FURTHER
photon emission computed tomography, cardiac magnetic resonance or positron emission tomography -computed tomography) or anatomical (coronary computed tomography angiography), depends on patient-related factors, pretest probability of significant CAD, symptom severity, and testing constraints. 188Patients requiring hospital admission for COVID-19 had a 3 to 4 times higher risk of MI in the 6 months postdischarge compared to outpatients. 189Whether currently available pretest probability scores for assessing obstructive CAD 190 in patients with acute or stable chest pain have good discriminatory power and whether early invasive strategy is useful in post-COVID-19 patients, especially after intensive care unit admission, when compared to non-COVID-19 patients is currently unknown.Thus, further studies are needed to develop personalized risk prediction algorithms for obstructive CAD in patients following acute COVID-19 and to identify appropriate diagnostic tests and primary and secondary treatment strategies.
chronic phases of COVID-19, an improved understanding of the overlap between the pathogenesis of SARS-CoV-2 and ASCVD could have actionable implications and allow for novel interventions directed at various steps in the pathogenesis.Additionally, the identification of costeffective screening and follow-up strategies across diverse risk groups will have significance beyond COVID-19 and enable the management of cardiovascular diseases in patients with other chronic infections.

TABLE 1
Studies Assessing the Risk of Atherosclerotic Cardiovascular Diseases (ASCVD) in Post-COVID-19 Patients

TABLE 2
Studies Evaluating Endothelial and Vascular Function in Post-COVID-19 Patients